1. Field of the Invention
The present invention relates to the treatment of tumor. In particular, the invention concerns an improved method for treating tumor, including cancer, which combines the administration of a chemotherapeutic agent and an antagonist of a gene product the expression of which is upregulated by the chemotherapeutic agent. The invention further concerns methods and means for the diagnosis and classification of tumors, and for the prognosis of the outcome of tumor treatment, and patient response to a particular treatment modality.
2. Description of the Related Art
Colorectal cancer is a leading cause of cancer mortality in Westernized countries accounting for over 50,000 deaths per year in the United States alone (Greenlee et al. Cancer statistics, 2001, CA Cancer J. Clin. 51:15-36). Approximately 50% of the patients diagnosed with colorectal cancer are treated successfully by surgical resection of the primary tumor. The remaining patients are either diagnosed with or, subsequent to surgery, progress to advanced disease where the 5-year survival rate drops precipitously due to invasion and metastasis of the primary lesion (Adjei, A. A. (1999), Br. J. Clin. Pharmacol. 48:265-277). These patients are candidates for systemic therapy, which is administered following surgery in the adjuvant setting or as palliative therapy for those ineligible for surgery. For the past four decades, 5-fluorouracil (5-FU) has served as first-line therapy for the treatment of colorectal cancer. 5-FU is frequently used in combination with drugs such as leucovorin, which enhance the inhibition of thymidylate synthase by 5-FU treatment (Poon et al. (1991) J. Clin. Oncol. 9, 1967-1972). However, inhibition of thymidylate synthase alone is likely approaching a limit with respect to efficacy in colorectal cancer (Ragnhammer et al. (2001) Acta Oncol 40, 282-308). More recently, irninotecan (CPT-11) was proven beneficial for patients that has failed 5-FU-based therapies and was subsequently tested in combination therapy with 5-FU (Saltz et al. (2000) N. Engl. J. Med. 343, 905-914). 5-FU/leucovorin plus CPT-11 is now recommended as first-line therapy in advanced colorectal cancer.
The most common group of cancers among women in the United States is breast cancer, which is a complex disease, including several distinct subtypes, which differ in their pathology and respond differently to standard treatment. Several groups have conducted gene expression studies to classify various breast cancer types or predict clinical outcome (see, e.g. Golub et al. (1999) Science 286:531-537; Bhattacharjae et al. (2001) Proc. Natl. Acad. Sci. USA 98:13790-13795; Chen-Hsiang et al. (2001), Bioinformatics 17 (Suppl. 1):S316-S322; Ramaswamy et al. (2001) Proc. Natl. Acad. Sci. USA 98:15149-15154 (2001); Martin et al. (2000) Cancer Res. 60:2232-2238; West et al., (2001) Proc. Natl. Acad. Sci. USA 98:11462-11467); Sorlie et al., (2001) Proc. Natl. Acad. Sci. USA 98:10869-10874; Yan et al., Cancer Res. 61:8375-8380 (2001); Van De Vivjer et al. (2002), New England Journal of Medicine 347: 1999-2009; Ahr et al, (2002) Lancet 359:131-2; van't Veer et al. (2002) Nature 415:530-6; Dowsett and Ellis (2003) Am. J. Clin. Oncol. 25:S34-9). It has been reported that 5-FU treatment trascriptionally activates certain genes in breast cancer cell lines and 5-FU resistant colorectal cancer cell lines (Maxwell et al. (2003) Cancer Res. 63:4602-4606).